Stability and low induction propensity of cefiderocol against chromosomal AmpC ß-lactamases of Pseudomonas aeruginosa and Enterobacter cloacae.

ABSTRACT

Objectives: The siderophore cephalosporin cefiderocol possesses in vitro activity against MDR Gram-negative bacteria. The stability of cefiderocol against serine- and metallo-type carbapenemases has been reported previously, but little is known about how cefiderocol interacts with chromosomal AmpC ß-lactamases. We investigated a number of features of cefiderocol, namely antibacterial activity against AmpC overproducers, stability against AmpC ß-lactamases and propensity for AmpC induction using Pseudomonas aeruginosa and Enterobacter cloacae. Methods: MICs were determined by broth microdilution according to CLSI guidelines. The MIC of cefiderocol was determined in iron-depleted CAMHB. Hydrolysis of the antibiotics was determined by monitoring the changes in the absorbance in the presence of AmpC ß-lactamase, and AmpC induction was evaluated by double disc diffusion and nitrocefin degradation assays. Results: The MICs of ceftazidime and cefepime for PAO1 increased 4- to 16-fold with inactivation of either ampD or dacB, whereas cefiderocol MICs were little affected by these inactivations (<2-fold increase). Cefiderocol has 17- and 740-fold lower affinity (higher Ki) to AmpCs of P. aeruginosa SR24-12 and E. cloacae P99, respectively, compared with ceftazidime. Both disc diffusion and nitrocefin degradation assays indicated that cefiderocol did not induce AmpC ß-lactamases of P. aeruginosa PAO1 and ATCC 27853 and E. cloacae ATCC 13047, whereas imipenem did. Conclusions: Cefiderocol showed in vitro activity against the AmpC-overproducing strains, low affinity for chromosomal AmpC ß-lactamases, and a low propensity of temporal induction of AmpC ß-lactamases of P. aeruginosa and E. cloacae. These features relating to chromosomal AmpC could explain the potent antibacterial activity of cefiderocol against drug-resistant strains producing AmpC ß-lactamases.